The gut incretin peptides, glucagon-like peptide 1 (GLP-1) and glucose-dependent insulinotropic peptide (GIP), are nutrient stimulated factors that regulate metabolism. In ? cell, incretins potentiate glucose-dependent insulin secretion and enhance ? cell mass through proliferation and anti-apoptotic actions. However, the majority of incretin peptides released by gut enteroendocrine cells become biologically inactive prior to reaching the pancreas, due to enzymatic cleavage by dipeptidyl peptidase-4 (DPP4). A thorough understanding of this biology has led to the development of two incretin-based therapies for the treatment of T2D; DPP4-resistant GLP-1 receptor agonists and DPP4 inhibitors (DPP4i). DPP4i potently increase the levels of active GLP-1 and GIP, promoting their interaction with their respective receptors (GLP-1R, GIPR). Mice with elimination of both incretin receptors do not secrete insulin or lower glucose in response to DPP4i, demonstrating the necessity of incretin peptides for the glucoregulatory actions of DPP4i. Despite the clinical use of DPP4i for over a decade, the cellular location of DPP4 inhibition remains unclear. One group has proposed that select DPP4 inhibition within the intestine to enhance local, but not systemic levels, of active incretins is sufficient to engage a gut-brain-pancreas axis to control glucose homeostasis. On the other hand, it was recently demonstrated that elimination of DPP4 from endothelial cells can reduce systemic DPP4 activity by ~50% and improve glucose homeostasis; whereas DPP4 elimination in the intestine did not impact glucose levels. In the current proposal, we will extend these findings and test the hypothesis that islets produce a significant portion of DPP4 activity, and accordingly, are a major target for DPP4i for the control of glucose homeostasis. Moreover, we hypothesize that enhancing biologically active incretin levels within the islet is essential for the glucoregulatory actions of DPP4i. To address this hypothesis, herein we describe specific aims utilizing innovative mouse models and isolated mouse and human islets to determine the extent to which ? cell GIPR and GLP-1R contribute to DPP4i glucose-lowering effect (aim 1) and the importance of islet DPP4i on insulin secretion (aim 2). The work described in this proposal will determine the importantce of islet-derived DPP4 and provide evidence for a local incretin system in the islet that controls glucose homeostasis.